In this proposal, we will try to achieve knowledge of the types of competitive interactions that occur in autoimmune and in infectious situations, both with unprimed naive populations and with primed memory cells. There are many elements involved in establishing repertoire choice, at the MHC and at the T cell levels. From an enormous repertoire of potential players, very often a small group of clones with characteristics that enhance disease emerge as "drivers" of the disease process. Often, such driver clones repeatedly occur in most individuals of the genetically restricted population. We would like to understand how such cells gain a competitive advantage. In the autoimmune encephalomyelitis (EAE) model of the B10.PL H-2u mouse, there are three transgenic lines of mouse all specific for the dominant determinant Acl-9 at the amino terminus of myelin basic protein. These transgenic cells will be followed for their early appearance, migratory properties, changing pattern of memory and adhesion surface markers, and cytokine/chemokine production and receptor patterns throughout the disease course. Are the drivers of autoimmunity always Th1 cells, always public, and of high affinity? The three clones will then be placed in competitive situations and we will ask under which conditions an advantage is gained by one of them. Does this advantage occur at the very outset of binding to the antigen presenting cell? Or during the early days of neonatal (lymphopenic) life? What evidence is there for in vivo clonal competition? In these studies, CDR3-1ength polymorphism will be used to follow the unique structures of these clonal receptors, and ELISAspot analysis as well as CFSE tracing of division, and confocal imaging of specific cluster formation will serve to study the competitive interactions. In the infectious disease world, the driver of disease, again found in many individuals, is more often than not, a Th2 cell, preventing the development of a successful defense. In the leishmanial system which we are studying, we plan to skew the response with adenovirus vectors containing cytokine genes, so that previously susceptible animals such as the BALB/c, treated with IL-12-bearing-adenovirus, now becomes resistant, and now we will explore the probability of defining a protective (set of) clone(s) in this mouse. Such protective clones could be compared to those found in the initially resistant B10.D2. Likewise, we will study the dominant determinant in the Leishmania homologue of mammalian RACK (=LACK) and its variants to examine the nature of pathogenic Th2 driver clones. In each of the opposite disease models of autoimmunity and infectious disease, it is of great interest that the defense of the body might be under the control of a particularly predominant clonal population.